De Toney Syndrome - Debre - Fanconi

This tubulopathy was identified by the Swiss pediatrician Fanconi among previously described by other researchers of individual parts of the disease. In 1931, he described glucosuria and albuminuria in a child with dwarfism and rickets , two years later de Toney added hypophosphatemia to the clinical picture, and soon Debre described aminoaciduria.

Most often, the syndrome is a component of other hereditary diseases: cystinosis , type I tyrosinemia, galactosemia , Wilson’s disease , fructose intolerance. Family variants of the syndrome are inherited autosomally recessively , autosomally dominantly or linked to the X chromosome ^[2] .

The type of inheritance is autosomal recessive, an autosomal dominant form with localization of the gene on the chromosome 15q15.3 is also distinguished. The expression of a mutant gene in a homozygous state varies significantly. There are sporadic cases due to a fresh mutation. It is believed that the disease is based on genetically determined defects in enzymatic phosphorylation in the renal tubules (combined tubulopathy ), enzyme deficiency of the 2nd and 3rd complexes of the respiratory chain - succinate dehydrogenase and cytochrome oxidase. Scientists classify the disease as mitochondrial disease .

Pathological changes are one of the options for secondary hyperparathyroidism . The main link of pathogenesis is the mitochondrial enzyme defect in the Krebs cycle , enzymatic tubulopathy , characterized by impaired reabsorption of glucose , amino acids , phosphates and bicarbonates in the tubules of the kidneys ^[1] . The loss of amino acids and bicarbonate contributes to the development of metabolic acidosis, against which bone resorption is enhanced and potassium and calcium reabsorption in the tubules of the kidneys is reduced, which leads to the development of hypokalemia and hypercalciuria. Loss of phosphorus leads to the development of rickets, and in older children and adults - to osteomalacia ^[2] .

Thus, a mitochondrial enzyme defect in the Krebs cycle leads to disruption of the energy supply processes for the reabsorption of phosphates, glucose and amino acids in the renal tubules and their increased excretion in the urine - the acid-base balance is disturbed, and metabolic acidosis and phosphate deficiency contribute to the destruction of bone tissue by the type of rickets-like changes skeleton and osteomalacia.

The first signs of the disease appear in the second half of life - children are sluggish, hypotrophic , appetite is sharply reduced, vomiting , low-grade fever , hypotension , thirst , polyuria , dehydration are observed ^[1] . The expanded symptom complex is formed by the second year of life. If the disease manifests itself in 5-6 years, the first signs are symptoms of osteomalacia , bone deformation and hypokalemic paralysis ^[2] . From the second year of life, the backlog of physical and intellectual development is revealed, generalized decalcification ^[1] occurs, which is manifested by bone deformities of the legs (valgus or varus), chest, forearms and humerus, and a decrease in muscle tone. X-ray revealed deformations of bones, spinal column, fractures ^[1] , systemic osteoporosis of varying severity, thinning of the cortical layer of the tubular bones, loosening of growth zones, lagging bone growth rates from the passport age of the child. Bones become brittle.

A laboratory examination reveals normo-or hypocalcemia , hypophosphatemia, an elevated level of alkaline phosphatase . As a result of a decrease in the reabsorption of bicarbonates in the tubules of the kidneys, hyperchloremic acidosis is observed against the background of an excess of parathyroid hormone and normo- or hypocalcemia. In the biochemical analysis of urine, aminoaciduria, glucosuria (at normal glycemia levels), sodium, hypocalceuria against the background of hyperphosphaturia are detected ^[1] .

Depending on the severity of clinical manifestations and metabolic disorders, two clinical and biochemical variants of the disease are distinguished:

1. The first is characterized by a significant delay in physical development, a severe course of the disease with pronounced bone deformities and often bone fractures, severe hypocalcemia (1.6-1.8 mmol / L), and a decrease in calcium absorption in the intestine.
2. In the second option, a moderate delay in physical development, a mild course with minor bone deformities, normocalcemia and normal absorption of calcium in the intestine are noted.

Biochemical disturbances

• decrease in blood calcium ;
• a decrease in the level of phosphorus in the blood;
• increase in alkaline phosphatase;
• the development of metabolic acidosis ( pH : 7.35 ... 7.25; BE: −10 ... -12 mmol / L) due to a defect in the reabsorption of bicarbonates in the proximal tubules;
• normal urinary calcium excretion;
• increased urine phosphate clearance, absorption of phosphate in the intestine does not suffer;
• the development of glucosuria (20-30 g / l and above);
• development of generalized hyperaminoaciduria;
• violation of the functions of ammonioacidogenesis - a decrease in titration acidity, an increase in urine pH greater than 6.0;
• the development of hypokalemia .

The outcome of the disease is the development of chronic renal failure ^[1] .

Differential diagnosis of de Tony-Debre-Fanconi syndrome is carried out with rickets and rickets-like diseases in children ^[1] . They also differentiate with a secondary syndrome that develops against the background of other hereditary and acquired diseases:

• Low syndrome
• juvenile nephronophysis ,
• cystinosis
• tyrosinemia
• galactosemia ,
• glycogenosis ,
• hereditary fructose intolerance,
• Rod-cone dystrophy,
• hepatobiliary dystrophy,
• myeloma
• amyloidosis
• Sjogren's syndrome ,
• nephrotic syndrome
• kidney transplant
• hyperparathyroidism , damage to the kidneys with salts of heavy metals,
• poisoning with medicinal substances, including vitamin D , lysol , etc.).

Basic principles - correction of electrolyte disturbances, shifts in acid-base balance , elimination of potassium and bicarbonate deficiency. They increase the intake of phosphorus with food, limit the intake of products including sulfur-containing amino acids , and prescribe large doses of vitamin D. For the treatment of cystinosis in order to suppress the accumulation of cystine in the tissues and proximal renal tubules, mercaptamine is used ^[2] . Prescribe calcium and vitamin D preparations , in case of chronic renal failure hemodialysis is performed ^[1] .

• Tubulopathies
• Bartter's syndrome

• E. V. Tush - Rickets and rickets-like diseases, N. Novgorod, 2007, p. 63-66